Chemical compounds

ABSTRACT

Phosphodiesterase (type III) inhibitors having the formula: ##STR1## wherein R 4  is hydrogen and A is a dihydro-1,2,4-triazin-3-one group or a dihydro-1,2,4-triazin-6-one group which are useful in stimulating cardiac activity and in treating congestive heart failure and bronchoconstriction, pharmaceutical compositions including these inhibitors, and methods of using these compounds to produce phosphodiesterase (type III) inhibition in mammals.

This is a divisional of application Ser. No. 06/918,425 filed Oct. 14,1986 now U.S. Pat. No. 4,906,628.

The present invention relates to pyridone derivatives and in particularto such compounds having a substituted phenyl group at the 1-position ofthe pyridone ring. This invention further relates to pharmaceuticalcompositions containing them and a method of stimulating cardiacactivity by administering them. The compounds of this invention areselective phosphodiesterase type III inhibitors and are of use incombatting such conditions wherein such inhibition is thought to bebeneficial. Thus the compounds of this invention are positive inotropicagents and vasodilators and are therefore of value in combattingcardiovascular disease, in particular congestive heart failure. Inaddition the compounds of this invention inhibit platelet aggregationand therefore have an antithrombotic effect. Furthermore the compoundsof this invention are bronchodilators and are therefore of use incombatting chronic reversible obstructive lung diseases such as asthmaand bronchitis. The major utility of the compounds of this invention isin the treatment of congestive heart failure, for such treatment thecompounds have a very desirable profile of activity.

Accordingly the present invention provides compounds of the formula (I):##STR2## and pharmaceutically acceptable salts thereof, wherein A is agroup of sub-formula (a), (b), (c) or (d): ##STR3## X is CHR¹, sulphur,oxygen or NH, R¹ is hydrogen, or R¹ and R² together form a bond,

R² is hydrogen or methyl, or R¹ and R² together form a bond,

R³ is hydrogen or together with R⁴ form a methylene or 1,2-ethanediylgroup,

Y is sulphur, oxygen or NH,

Z is sulphur or oxygen,

R⁴ is hydrogen or together with R³ form a methylene or 1,2-ethanediylgroup,

with the proviso that X is CHR¹ or sulphur when R³ together with R⁴ forma methylene or 1,2-ethanediyl group.

Suitably A is a group of sub-formula (a) thus forming a pyridazin-3-one,dihydropyridazin-3-one, 1,3,4-thiadiazin-2-one, 1,3,4-oxadiazin-2-one,dihydro-1,2,4-triazin-3-one, dihydroindeno[1,2-c]pyridazin-3-one,indeno[1,2-c]pyridazin-3-one, tetrahydrobenzo[h]cinnolin-3-one,dihydrobenzo[h]cinnolin-3-one,dihydroindeno[1,2-e][1,3,4]thiadiazin-2-one ordihydronaphtho[1,2-e][1,3,4]thiadiazin-2-one ring system.

Suitably X is CHR¹, sulphur or NH, preferably X is CHR¹ or NH.

Particularly X is CHR¹.

Suitably when X is CHR¹, R¹ and R² together form a bond.

Preferably R² is methyl.

Suitably R³ and R⁴ together form a methylene group.

Preferably R³ is hydrogen.

Suitably A is a group of sub-formula (b) thus forming a1,3,4-thiadiazin-5-one, 1,3,4-oxadiazin-5-one or dihydro-1,2,4-triazin-6-one ring system.

Suitably Y is sulphur or oxygen, preferably Y is sulphur.

Suitably A is a group of sub-formula (c) thus forming a pyrazin-2-onering system.

Suitably A is a group of sub-formula (d) thus forming a1,3,4-thiadiazol-2-one or 1,3,4-oxadiazol-2-one ring system.

Particular compounds of this invention are:

5-methyl-6-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-3(2H) -pyridazinone,

2-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-4H,6H-1,3,4-thiadiazin-5-one,

2-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-4H,6H-1,3,4-oxadiazin-5-one,

6-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one,

6-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one,

7-(4-oxo-1,4-dihydropyridin-1-yl)-9a-methyl-9,9a-dihydroindeno[1,2-e][1,3,4]thiadiazin-2(3H)-one,

7-(4-oxo-1,4-dihydropyridin-1-yl)-9,9a-dihydroindeno-[1,2-e][1,3,4]thiadiazin-2(3H)-one,

5-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-6-methyl-3H,6H-1,3,4-thiadiazin-2-one,

5-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-2(1H) -pyrazinone,

7-(4-oxo-1,4-dihydropyridin-1-yl)-[5H]indeno[1,2-c]-pyridazin-3(2H)-one,

8-(4-oxo-1,4-dihydropyridin-1-yl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,

5-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-1,3,4-thiadiazol-2(3H)-one,and

5-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-1,3,4-oxadiazol-2(3H)-one,

and pharmaceutically acceptable salts thereof.

This invention covers all tautomeric forms of compounds of formula (1).This invention also covers all optical isomets of the compounds offormula (1) in the resolved and racemic states in which R² is hydrogenand R³ together with R⁴ form a methylene or 1,2-ethanediyl group, or R²is methyl. In particular when R² is methyl and R¹, R³ and R⁴ are allhydrogen the (R) isomer of a compound of the formula (1) is preferred.When R² is methyl, R³ and R⁴ are both hydrogen and X is sulphur, oxygenor NH the (S) isomer of a compound of the formula (1) is preferred.

Compounds of the formula (1) may form pharmaceutically acceptable saltsWith acids such as hydrochloric, hydrobromic, sulphuric, phosphoric,methanesulphonlc and ethanesulphonic acids.

Compounds of the formula (1) wherein X is CHR¹ and R¹ and R² togetherform a bond or A is a group of sub-formula (c) or (d) may formpharmaceutically acceptable salts with metal ions, such as alkali metalsfor example sodium and potassium or alkaline earth metals for examplecalcium and magnesium, or With an ammonium ion.

In order to use a compound of the formula (1) or a pharmaceuticallyacceptable salt thereof for the treatment of humans and other mammals itis normally formulated in accordance with standard pharmaceuticalpractice as a pharmaceutical composition.

Compounds of formula (1) and their pharmaceutically acceptable salts maybe administered in standard manner for the treatment of the indicateddiseases, for example orally, parenterally, trans-dermally, rectally,via inhalation or via buccal administration.

Compounds of formula (1) and their pharmaceutically acceptable saltswhich are active when given orally or via buccal administration can beformulated as liquids syrups, tablets, capsules and lozenges. An oralliquid formulation will generally consist of a suspension or solution ofthe compound or salt in a liquid caccier for example, ethanol, glycerineor water with a flavouring or colouring agent. Where the composition isin the form of a tablet, any pharmaceutical carrier routinely used forpreparing solid formulations may be used. Examples of such carriersinclude magnesium stearate, starch, celluloses, lactose and sucrose.Where the composition is in the form of a capsule, any routineencapsulation is suitable, for example using the aforementioned carriersin a hard gelatin capsule shell. Where the composition is in the form ofa soft gelatin shell capsule any pharmaceutical carrier routinely usedfor preparing dispersions or suspensions may be considered, for exampleaqueous gums, celluloses, silicates or oils and are incorporated in asoft gelatin capsule shell.

Typical parenteral compositions consist of a solution or suspension ofthe compound or salt in a sterile aqueous or non-aqueous carrieroptionally containing a parenterally acceptable oil, for examplepolyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, orsesame oil.

A typical suppository formulation comprises a compound of formula (1) ora pharmaceutically acceptable salt thereof which is active whenadministered in this way, with a binding and/or lubricating agent, forexample polymeric glycols, gelatins, cocoa-butter or other low meltingvegetable waxes or fats.

Typical transdermal formulations comprise a conventional aqueous ornon-aqueous vehicle, for example a cream, ointment, lotion or paste orare in the form of a medicated plaster, patch or membrane.

Typical compositions for inhalation are in the form of a solution,suspension or emulsion that may be administered in the form of anaerosol using a conventional propellant such as dichlorodifluoromethanaor trichlorofluoromethane, or are in the form of a powder forinsufflation.

Preferably the composition is in unit dosage form, for example a tablet,capsule or metered aerosol dose, so that the patient may administer tohimself a single dose.

Each dosage unit for oral administration contains suitably from 0.001mg/Kg to 3 mg/Kg. and preferably from 0.005 mg/Kg to 1.5 mg/Kg. and eachdosage unit for parenteral administration contains suitably from 0.001mg/Kg to 1 mg/Kg, of a compound of formula (1) or a pharmaceuticallyacceptable salt thereof calculated as the free base.

The daily dosage regimen for oral administration is suitably about 0.001mg/Kg to 12 mg/Kg. of a compound of formula (1) or a pharmaceuticallyacceptable salt thereof calculated as the free base. The daily dosageregimen for parenteral administration is suitably about 0.001 mg/Kg to 4mg/Kg. for example about 0.005 mg/Kg to 1 mg/Kg. of a compound of theformula (1) or a pbarmaceutlcally acceptable salt thereof calculated asthe free base. The active ingredient may be administered from 1 to 4times a day, sufficient to increase cardiac output. The compositions ofthe present invention have Positive inotropic activity and vasodilatotactivity and ate of use in the treatment of cardiovascular diseaseswhich can be treated by compounds having either or both of theseactivities. One such disease condition is congestive heart failure. Thecompounds of the invention are also bronchodilators and are useful inchronic reversible obstructive lung disease for example asthma andbronchitis. Such conditions can be treated by administration orally,topically, rectally, parenterally or by inhalation. For administrationby inhalation dosages are controlled by a valve, are administered asrequired and for an adult are conveniently in the range 0.1-5.0 mg of acompound of the formula (1) or a pharmaceutically acceptable saltthereof.

The compounds of this invention may be co-administered with otherpharmaceutically active compounds, for example in combination,concurrently or sequentially. Conveniently the compounds of thisinvention and the other active compound or compounds are formulated in apharmaceutical composition. Examples of compounds which may be includedin pharmaceutical compositions with the compounds of the formula (1) arevasodilators for example hydralazine, angiotensin converting enzymeinhibitors for example captopril, anti-anginal agents for exampleisosorbide nitrate, glyceryl trinitrate and pentaerythritoltetranitrate, anti-arrhythmic agents for example quinidine, procainamideand lignocaine, cardioglycosides for example digoxin and digitoxin,calcium antagonists for example verapamil and nifedipine, diuretics suchas thiazides and related compounds for example bendrofluazide,chlorothiazide, chlorothalidone, hydrochlorothiazide, and otherdiuretics for example frusemide and triamterene, and sedatives forexample nitrazepam, flurazepam and diazepam.

The compounds of the formula (1) or pharmaceutically acceptable saltsthereof can be prepared by a process which comprises:

a) reacting a compound of the formula (2): ##STR4## wherein R⁴ and A areas hereinbefore defined, with 4H-pyran-4-one or a chemical equivalentthereof;

b) reacting a compound of the formula (3): ##STR5## wherein R⁴ and A areas hereinbefore defined, with 4-hydroxypyridine;

c) for compounds wherein X is CHR¹ and R¹ is as hereinbefore defined,reacting a compound of the formula (4): ##STR6## wherein R², R³ and R⁴are as hereinbefore defined, B is ##STR7## R is a group R¹ ashereinbefore defined or R can be OH when R² is hydrogen, and X¹ is adisplaceable group, with hydrazine or a chemical equivalent thereof andwhen R is OH followed by dehydration;

d) for compounds wherein X is NH, reacting a compound of the formula(5): ##STR8## wherein R² is as hereinbefore defined, B is and X² is aleaving group, with hydrazine or a chemical equivalent thereof.

e) for compounds Wherein X is sulphur, reacting a compound of theformula (6): ##STR9## wherein X³ is halo, R², R³ and R⁴ are ashereinbefore defined, provided that R² is hydrogen when R³ together withR⁴ forms a methylene or 1,2-ethanediyl group, with a compound of theformula (7): ##STR10## wherein R⁵ is C₁₋₆ alkyl;

f) for compounds wherein X is sulphur, cyclising a compound of theformula (8): ##STR11## wherein R², R³ and R⁴ are as hereinbefore definedand R⁶ is optionally protected amino, in the presence of acid,

g) for compounds wherein X is oxygen, cyclising a compound of theformula (9): ##STR12## wherein R² and R⁵ are as hereinbefore defined;

h) for compounds wherein Y is sulphur, treating a compound of theformula (10): ##STR13## with a haloacetic acid;

i) for compounds wherein Y is oxygen, cyclising a compound of theformula (11): ##STR14## wherein X³ is halo; or

j) for compounds wherein Y is NH, treating a compound of the formula(12): ##STR15## wherein R⁵ is as hereinbefore defined, with hydrazine ora chemical equivalent thereof;

and thereafter optionally;

i) dehydrogenating a compound of the formula (1) wherein X is CHR¹, R¹is hydrogen and R² is hydrogen to the corresponding compound wherein R¹and R² together form a bond,

ii) forming a pharmaceutically acceptable salt.

The reaction between a compound of the formula (2) and 4H-pyran-4-one ora chemical equivalent thereof is suitably performed at ambient orelevated temperature, for example 15°-190° C., preferably 30°-100° C. orat the reflux temperature of a suitable solvent. The reaction isconveniently performed in a solvent such as a C₁₋₄ alkanol, for exampleethanol or n-propanol, aqueous or glacial acetic acid, water ordimethylsulphoxide. Suitably the reaction is performed under acidicconditions, preferably the reaction is carried out in water acidifiedwith hydrochloric acid or acetic acid.

By a chemical equivalent of 4H-pyran-4-one we mean a reagent which canbe reacted with a primary amine to afford a N-substituted pyridin-4-onecompound. Examples of chemical equivalents of 4H-pyran-4-one includechelidonic acid (13), 1,5-bis(dimethyIamino)-1,4-pentadien-3-one (14)(Synth. Commun. 1983, 13, 1137) or 1,4-pentadiyn-3-one (15) (Ber. 1963,96, 2504): ##STR16##

The reaction between a compound of formula (2) and chelidonic acidcomprises two decarboxylation steps. Preferably the reaction isperformed in a similar manner to that described by Katritzky et al.,Journal Heterocyclic Chemistry 21, 1465-7, (1984), for example indimethylsulphoxide at reflux.

The reaction between a compound of the formula (3) and 4-hydroxypyridineis conveniently performed at an elevated temperature, for examplebetween 80° to 150° C. Suitably the reaction is performed in an aproticsolvent, such as dimethylformamide or N-methylpyrrolidin-2-one, in thepresence of a base such as sodium hydride or potassium tert-butoxide.

The reaction between compounds of the formulae (4), (5) or (12) andhydrazine or a chemical equivalent thereof is suitably performed atambient or elevated temperature, for example 15° C.-120° C., preferablyabout 30° C.-80° C. or at reflux temperature of a suitable solvent. Thereaction is conveniently performed in a solvent such as water, a C₁₋₄alkanol for example methanol, ethanol or n-propanol, or aqueous orglacial acetic acid. Suitably in the compounds of the formula (4) X¹ ishydroxy, C₁₋₆ alkoxy, amino or C₁₋₆ alkylamino. When R is OH in thecompounds of the formula (4) dehydration either occurs during thereaction or an additional step of dehydration (e.g. treatment with anacid e.g. hydrochloric acid in acetic acid) is carried out. Suitably ina compound of the formula (5) X² is C₁₋₆ alkoxy. Suitably in a compoundof the formula (12) R⁵ is methyl or ethyl.

By a chemical equivalent of hydrazine we mean hydrazine hydrate,hydrazine ethanolate or a similar solvate. Preferably hydrazine is usedin the form of hydrazine hydrate.

Suitably the reaction of the compounds of the formulae (6) and (7) isperformed in an organic solvent for example a C₁₋₄ alkanol such asethanol, or in acetonitrile. The reaction is conveniently performed atan elevated temperature for example under reflux conditions. Suitably X³is bromo or chloro, preferably bromo. Suitably R⁵ is methyl.

Suitably the cyclisation of a compound of the formula (8) is performedin an aqueous inorganic acid, for example hydrochloric acid, or in anorganic solvent containing an aqueous inorganic acid, for example in aC₁₋₄ alkanol, such as ethanol in admixture with hydrochloric acid. Thecyclisation is conveniently performed at an elevated temperature forexample 60° C. to 140° C., preferably at reflux temperature forconvenience.

The cyclisation may be performed on a compound of the formula (8)wherein R⁶ is amino, or a protected variant of the compound of theformula (8), for example protected on the hydrazine function by anacid-labile protecting group for example isopropylidene or benzylidenei.e. R⁶ is --N═C(CH₃)₂ or --N═CHC₆ H₅.

Suitably the cyclisation of a compound of the formula (9) is performedin the presence of a base, for example sodium ethoxide, in a solvent,for example ethanol, at ambient temperature.

A compound of the formula (10) is suitably treated with chloro- orbromoacetic acid in aqueous solution in the presence of a base. forexample sodium hydroxide, at ambient temperature, followed byacidification of the reaction mixture with for example acetic acid.

In general the cyclisation of a compound of the formula (11) isperformed in the presence of a base, for example sodium hydride, in adipolar aprotic solvent such as dimethylformamide, or with an alkalimetal carbonate such as potassium carbonate in acetone, at an elevatedtemperature for example under reflux conditions. Suitably X³ in acompound of the formula (11) is bromo or chloro.

Methods of dehydronenation of a compound of the formula (1) wherein X isCHR¹, and R¹ and R² are both hydrogen, include treatment withm-nitrobenzene sulphonic acid and base or with bromine in acetic acid.

The compounds of the formulae (2) and (3) wherein X is CHR¹, and R¹, R²,R³ and R⁴ are as hereinbefore defined are known, or preparable inconventional manner, from Curran et al., J. Medicinal Chemistry, 17,p273, (1974) and European Patent Applications 0150937 and 0181145.

The compounds of the formulae (2) and (3) wherein X is oxygen, sulphuror NH, and R³ and R⁴ are both hydrogen, or Y is oxygen, sulphur or NHare known, or preparable in conventional manner from European PatentApplications 52442 and 123254.

The compounds of the formulae (2) and (3) wherein X is sulphur and R³together with R⁴ is a methylene or 1,2-ethanediyl group are known, orpreparable in conventional manner from European Patent Application145236.

The compounds of the formulae (2) and (3) wherein A is a pyrazinone ringare known, or preparable in conventional manner from European PatentApplication 96517.

The compounds of the formula (2) wherein Z is oxygen or sulphur can beprepared by reducing a compound of the formula (16): ##STR17## wherein Zis oxygen or sulphur.

Suitably when Z is sulphur the reduction is performed with sodiumsulphide in a mixture of dioxane and water. Suitably when Z is oxygenthe reduction is performed with hydrogen in the presence of palladium oncarbon in a suitable solvent such as ethanol.

The compounds of the formulae (3) and (16) wherein Z is sulphur areknown or preparable in conventional manner from Eur. J. Med. Chem. -Chim. Ther , 1985, 20, No 1, 33-36.

The compounds of the formulae (3) and (16) wherein Z is oxygen aresuitably prepared from a compound of the formula (17): ##STR18## whereinC is fluoro or nitro and R⁵ is C₁₋₆ alkyl, by succesive treatment withi) hydrazine or a chemical equivalent thereof, andii)carbonyldiimidazole.

The (-) and (+) isomers of a compound of the formula (2) wherein R² ishydrogen and R³ together with R⁴ forms a methylene or 1,2-ethanediylgroup, or R² is methyl can be separated by passage of racemic compoundover a chiral phase chromatography column. The appropriate fractions arecollected. rechromatographed as necessary, solvent is evaporated and thedesired isomer isolated in conventional manner. The (-) and (+) isomersof a compound of the formula (2) wherein R² is methyl and R¹, R³ and R⁴are all hydrogen are respectively the (R) and (S) isomers.

The resolved form of a compound of the formula (1) can be prepared byreaction of the corresponding resolved form of a compound of formula (2)with 4H-pyran-4-one or a chemical equivalent thereof.

The compounds of the formula (4) wherein B is ##STR19## can be preparedby the following general routes:

a) by reaction of a compound of the formula (18): ##STR20## wherein R,R², R³, R⁴ and X¹ are as hereinbefore defined, with 4H-pyran-4-one or achemical equivalent thereof in an analogous manner to that described forreacting a compound of the formula (2) with 4H-pyran-4-one or a chemicalequivalent thereof; or

b) for compounds wherein X¹ is amino, hydroxy or C₁₋₆ alkoxy, byreaction of a compound of the formula (4): ##STR21## wherein B isfluoro, X¹ is amino, hydroxy or C₁₋₆ alkoxy and R, R², R³ and R⁴ are ashereinbefore defined, with 4-hydroxypyridine. Suitably the reaction isperformed at an elevated temperature, for example at about 80-150° C.,particularly at 100-140° C. Suitably the reaction is performed in anaprotic solvent, such as dimethylformamide, preferably inN-methylpyrrolidin-2-one in the presence of a base such as sodiumhydride or potassium tert-butoxide. Alternatively the reaction isperformed in an aqueous C₁₋₄ alkanol, for example n-butanol, in thepresence of a base such as sodium hydroxide at an elevated temperature,for example under reflux conditions. Preferably when X¹ is hydroxy thereaction is performed in water in the presence of a base such as sodiumbydroxide at an elevated temperature, for example under refluxconditions or in an autoclave at a temperature of about 140° C.

The compounds of the formula (4) wherein B is fluoro or ##STR22## can beprepared by the following general routes:

a) for compounds wherein X¹ is hydroxy, R is hydroxy and R² is hydrogen,or R and R² together form a bond, by reaction of a compound of theformula (19): ##STR23## wherein B is fluoro or ##STR24## and R³ and R⁴are as hereinbefore defined, with glyoxylic acid or a chemicalequivalent thereof. By a chemical equivalent of glyoxylic acid we mean asolvate such as the hydrate or a combination of reagents which cangenerate glyoxylic acid in situ e.g. a mixture of tartaric acid andsodium metaperiodate. Preferably a compound of the formula (19) is fusedwith glyoxylic acid to afford a compound of the formula (4) which isdissolved in aqueous ammonia to pH 8 and reacted with hydrazine at anelevated temperature to give a compound of the formula (1) or (3)wherein X is CHR¹, and R² together form a bond, and R³ and R⁴ are ashereinbefore defined;

b) for compounds wherein X¹ is C₁₋₆ alkoxy or hydroxy and R is hydrogen,by formation of the sodium derivative of a compound of the formula (20):##STR25## wherein B is fluoro or ##STR26## and R², R³ and R⁴ are ashereinbefore defined, and reaction with a C₁₋₆ alkyl bromoacetate,followed by optional hydrolysis. Suitably the sodium derivative isformed by reaction with sodium hydride. Preferably the alkylbromoacecate is ethyl bromoacetate. Suitably the hydrolysis is carriedout under aqueous acidic conditions;

c) for compounds wherein X¹ is hydroxy or amino, R is hydrogen and R²,R³ and R⁴ are as hereinbefore defined provided that R² is hydrogen whenR³ together with R⁴ forms a methylene or 1,2-ethanediyl group, byreaction of a compound of formula (20) as hereinbefore defined providedthat R² is hydrogen when R³ together with R⁴ forms a methylene or1,2-ethanediyl group, with a Mannich reagent to give an intermediate offormula (21) in which R⁵ is C₁₋₆ alkyl, followed by optionalquaternisation to give an intermediate of formula (22) in which X⁴ is ahalide or methylsulphate, treatment with potassium cyanide to give anitrile of formula (23) and hydrolysis. ##STR27##

Examples of Mannich reagents are a mixture of dimethylamine andformaldehyde, and bis(dimethylamino)methane. Preferably a slight excessof Mannich reagent is used, for example 1,3 molar equivalents.Preferably the reaction is carried out in the presence of an inertorganic solvent for example C₁₋₄ alkanols. Preferably the reaction iscarried out at an elevated temperature, for example 60-100° C.,preferably at the reflux temperature of the reaction mixture.

Preferably quaternisation is carried out by reaction with an alkylhalide or a dialkyl sulphate.

Preferably the treatment with potassium cyanide is carried out in thepresence of a solvent, for example water, C₁₋₄ alkanols, acetic acid andaqueous mixtures thereof.

The acids (4) wherein X¹ is hydroxy can be prepared by hydrolysis of thenitriles (23), using aqueous acids or bases, carried out at elevatedtemperatures, e.g. 100° C.

The amides (4) wherein X¹ is amino are prepared by hydrolysis of thenitriles (23), using concentrated acids, preferably concentratedsulphuric acid, carried out at moderate temperatures;

d) for compounds wherein X¹ is hydroxy and R is hydrogen, by reaction ofa compound of the formula (24) wherein B is fluoro or ##STR28## R², R³and R⁴ are as hereinbefore defined and X⁵ is a leaving group, with thesodium derivative of a dialkyl malonate (preferably diethylmalonate) togive a compound of the formula (25) wherein R⁵ is C₁₋₆ alkyl which isthen hydrolysed and decarboxylated.

Suitably X⁵ is chloro or bromo, preferably chloro.

Suitably the hydrolysis is carried out under aqueous acidic conditions,preferably when B is fluoro with a co-solvent such as dioxan. ##STR29##

The compounds of the formula (24) wherein X⁵ is bromo can be prepared bybromination of a compound of the formula (20). Suitably the brominationis carried out using bromine or N-bromosuccinimide in a suitablesolvent, preferably using bromine in acetic acid.

The compounds of the formula (24) wherein X⁵ is chloro and R³ and R⁴ areboth hydrogen can be prepared by acylation of fluorobenzene orN-phenylpyridin-4-one with an α-chloroacylchloride of formula (26):##STR30## wherein R² is hydrogen or methyl.

Suitably the acylation is carried out in the presence of a Lewis acidcatalyst, such as aluminium trichloride. Suitably the acylation iscarried out in a suitable solvent, such as dichloromethane ortrichlorobenzene.

The compounds of the formula (20) wherein B is ##STR31## can be preparedby the following general routes:

a) by reaction of a compound of the formula (20) wherein B is fluorowith 4-hydroxypyridine. Suitably the reaction is performed at anelevated temperature, for example at about 80-150° C. Suitably thereaction is performed in an aprotic solvent, such as dimethylformamide,or N-methylpyrrolidin-2-one in the presence of a base such as sodiumhydride or potassium tert-butoxide, or

b) by reaction of a compound of the formula (27): ##STR32## wherein R²,R³ and R⁴ are as hereinbefore defined, with 4H-pyran-4-one or a chemicalequivalent thereof in analogous manner to the reaction of a compound ofthe formula (2) with 4H-pyran-4-one or a chemical equivalent thereof.

Compounds of the formula (20) wherein B is fluoro and compounds of theformulae (18) and (27) are known, or preparable in conventional manner,from Curran et al., J. Medicinal Chemistry, 17, p273, (1974) andEuropean Patent Applications 0150937 and 0181145.

A compound of the formula (5) wherein B is ##STR33## can be prepared byreacting a compound of the formula (5) wherein B is fluoro with4-hydroxypyridine, in an analogous manner to that hereinbefore describedfor the reaction of a compound of the formula (4) wherein B is fluorowith 4-hydroxypyridine.

A compound of the formula (5) wherein B is ##STR34## or fluoro can beprepared from a compound of the formula (24) wherein B, R² and X⁵ are ashereinbefore defined and R³ and R⁴ are both hydrogen, in a similarmanner to that described in EP-52442, for example by reaction withsodium azide, followed by reduction of an azido intermediate to form anamino compound which is reacted with an alkyl chloroformate.

A compound of the formula (8) can be prepared by reacting a compound ofthe formula (24) wherein B is ##STR35## with a compound of the formula(28):

    M.sup.+-- OCSNHR.sup.6                                     ( 28)

wherein R⁶ is as hereinbefore defined and M⁺ is a counter-ion, forexample an alkali metal ion such as potassium or sodium or is anammonium ion, in a similar manner to that described in EP-52442 andEP-A-145236.

A compound of the formula (6) (which is a compound of the formula (24)wherein B is ##STR36## X⁵ is halo and R², R³ and R⁴ are as hereinbeforedefined provided that R² is hydrogen when R³ together with R⁴ forms amethylene or a 1,2-ethanediyl group) can be prepared as hereinbeforedescribed for a compound of the formula (24).

A compound of the formula (9) can be prepared from a compound of theformula (24) wherein B is ##STR37## and R³ and R⁴ are both hydrogen in asimilar manner to that described in EP-52442, for example by reactionwith potassium acetate in acetic acid to afford an acetoxy compoundwhich is hydrolysed by treatment with aqueous hydrochloric acid and isthen reacted with an alkyl carbazate.

A compound of the formula (10) can be prepared from 4-(4-oxo-14-dihydropyridin-1-yl)benzaldehyde in a similar manner to that describedin EP-52442, for example by successive treatment with i) sulphur andpiperidine, ii) bromoacetic acid iii) hydrogen sulphide and iv)hydrazine or a chemical equivalent thereof.4-(4-Oxo-1,4-dihydropyridin-1-yl)benzaldehyde can be prepared byreacting 4-fluorobenzaIdehyde with 4-hydroxypyridine.

A compound of the formula (11) can be prepared from ethyl4-fluorobenzoate in a similar manner to that described in U.S. Pat. No.4,508,718 and EP-52442, for example by successive treatment with i)4-hydroxypyridine in the presence of a base such as sodium hydride, ii)hydrazine or a chemical equivalent thereof and iii) a haloacetylhalidesuch as chloroacetylchloride in the presence of a base such as potassiumcarbonate or triethylamine.

A compound of the formula (12) can be prepared in a similar manner tothat described in EP-5244, for example from4-(4-oxo-1,4-dihydropyridin-1-yl)benzoyl chloride by successivetreatment with i) an alkyl glycinate and ii) an oxoniumtetrafluoroborate of the formula (R⁵)₃ OBF₄ wherein R⁵ is C₁₋₆ alkyl.Suitably the 4-substituted benzoyl chloride is prepared by treating4-aminobenzoic acid with 4H-pyran-4-one or a chemical equivalent thereofto afford 4-(4-oxo-1,4-dihydropyridin-1-yl)benzoic acid which is treatedwith thionyl chloride.

Pharmaceutically acceptable acid addition salts of the compounds of theformula (1) may be prepared from the corresponding base of the compoundsof the formula (1) in conventional manner. For example the base may bereacted with an acid in a C₁₋₄ alkanol, or an ion-exchange resin may beused. The salts of the compounds of the formula (1) may beinterconverted using ion-exchange resins. Non-pharmaceuticallyacceptable salts are therefore of use as they can be convertad topharmaceutically acceptable salts.

Pharmaceutically acceptable base addition salts of the compounds of theformula (1) may be prepared by standard methods, for example by reactinga solution of the compound of the formula (1) with a solution of thebase.

The following biological test methods, data, Description and Examplesserve to illustrate this invention.

CARDIAC STIMULANT ACTIVITY IN VIVO (ANAESTHETISED CATS)

In anaesthetised cats pretreated with a ganglion blocker (mecamylamineor pempidine) and propranolol, the compounds of the Examples causeincreases in left ventricular dp/dt max (this is an index of leftventricular contractility) when administered intravenously. The dose toincrease left ventricular dp/dt max by 50% is given as the ED₅₀.

    ______________________________________                                                        ED.sub.50   Relative #                                        Compound of Example                                                                           (micromol/kg)                                                                             Duration                                          ______________________________________                                        1               0.04        ***                                               2               0.40        *                                                 3               0.47        *                                                 4               0.06        *                                                 5               0.22        ***                                               6               0.23        *                                                 7               0.11        ***                                               8               0.07        *                                                 9               0.05        *                                                 10              0.07        *                                                 13              0.78        *                                                 14              0.82        *                                                 Amrinone        5.6         *                                                 ______________________________________                                         #Relative duration was estimated in the anaesthetised cats following the      i.v. administration: ***long: *short                                     

Minimal changes in blood pressure or heart rate were observed.

CARDIAC STIMULANT ACTIVITY IN VIVO (CONSCIOUS DOGS)

The compound of Example 1 increased left ventricular dp/dt max inconscious dogs after intravenous administration at doses below 0.02mg/kg. Oral administration caused positive inotropic responses at dosesof 0.05 mg/kg and below. These positive inotropic responses persistedfor more than 3 hours (maximum duration of measurement) without changesin blood pressure or heart rate. Therefore this compound is particularlybeneficial with regard to `force-rate` selectivity. In contrast amrinoneis less active and is of shorter duration.

INHIBITION OF PHOSPHODIESTERASES

Three peaks of cyclic nucleotide phosphodiesterase activity [PDE (PeakI), PDE (Peak II) and PDE (Peak III)] from cat heart were separated bychromatography on DEAE Sepharose CL-6B (Diethylaminoethyl Cellulose witha bead size of 45-165 microns). Sepharose is a registered trademark ofpharmacia Fine Chemicals Inc. The high-speed supernatant from a catheart homogenate (2 g tissue in 20 ml 20 mM PIPES(Piperazine-N-N'-bis[2-ethanesulfonic acid]), 50 mM Na acetate, pH 6.5)was applied to a 15×1.5 cm column of DEAE-Sepharose equilibrated withthe homogenisation buffer. The PDE activities were eluted with agradient of 0.05-1 M Na acetate in 20 mM PIPES. There were three majorpeaks which had the following characteristics:

    ______________________________________                                                 50 μg/ml calmodulin                                               Substrate                                                                              (+ = added)    Km(μM) Relative V.sub.max                          ______________________________________                                        PDE (Peak I) - eluted at 0.15M Na acetate                                     cyclic AMP                                                                             -              0.5       1                                           cyclic GMP                                                                             -              1.8       1.1                                         cyclic AMP                                                                             +              0.7       6.3                                         cyclic GMP                                                                             +              1.4       7.2                                         PDE (Peak II) - eluted at 0.3M Na acetate                                     cyclic AMP              6         1                                           cyclic GMP              28        0.2                                         PDE (Peak III) - eluted at 0.5M Na acetate                                    cyclic AMP              0.6       1                                           cyclic GMP              2.9       0.4                                         ______________________________________                                    

PDE (Peak I) has high affinity for cyclic AMP and cyclic GMP and ischaracterised by an activation by Ca²⁺ /calmodulin complex.

PDE (Peak II) demonstrates relatively low affinities for both cyclic AMPand cyclic GMP and is not affected by Ca²⁺ /calmodulin complex.

PDE (Peak III) has high affinity for cyclic AMP. It can also hydrolysecyclic GMP though the preferred substrate is cyclic AMP. This activityis also insensitive to Ca²⁺ /calmodulin activation.

ENZYME ASSAY

The enzyme was assayed by incubation at 37° for 4-30 min in 50 mM Tris,5 mM MgCl₂, pH 7.5 with [3-H] cyclic nucleotide (4×10⁵ disintegrationsmin⁻¹) and [14-C] nucleotide 5' monophosphate (3×10³ disinteqrationsmin⁻¹). The assay was stopped by boiling, and the [3-H] 5'monophosphateproduct separated from substrate on boronate columns (Davis, C. W. andDaly, J. W. (1979) J. Cyclic Nucleotide Res., 5 65-74). The reactionmixture was diluted with 0.5 ml 100 mM HEPES(N-2-Hydroxyethpiperazine-N'-2-ethanesulfonic acid), 100 mM NaCl, pH8.5, and applied to the column. The column was extensively washed withthe same buffer, and the 5' nucleotide eluted with 6 ml 0.25M aceticacid. The recovery of producer as judged by [14-C] recovery wasapproximately 80%. All assays were linear with time of incubation andconcentration of enzyme over the range used in these experiments.

CALCULATION OF IC₅₀ VALUES

IC₅₀ values (the concentration of inhibitor required for 50% inhibitionof activity) were obtained for PDE (Peak III) by incubation of theenzyme at 1 μM cyclic AMP, and a range of inhibitor concentrations from0.1×IC₅₀ to 100×IC₅₀.

    ______________________________________                                        Compound of Example                                                                             IC.sub.50 × 10.sup.-6 M                               ______________________________________                                        1                 0.41                                                        2                 5.09                                                        3                 3.99                                                        4                 1.59                                                        5                 4.33                                                        6                 1.75                                                        7                 0.54                                                        8                 1.32                                                        9                 1.25                                                        10                0.44                                                        11                2.64                                                        13                6.60                                                        14                2.26                                                        16                0.23                                                        17                2.58                                                        Amrinone          51.8                                                        Milrinone         2.2                                                         ______________________________________                                    

SPECIFICITY

The compounds described in the Examples showed no inhibition at up to10⁻⁴ M when incubated with PDE (Peak I) and either no or weak inhibitionwith respect to PDE (Peak II) i.e. they were selective PDE (Peak III)inhibitors. This specificity is an indication that the compounds arelikely to have a force/rate selectivity in their cardiac stimulantactivity with a low potential for inducing arrythmias.

VASODILATOR ACTIVITY

The compounds of the Examples were tested in autoperfused anaesthetisedcat hindquarters (autoperfused at constant blood flow). The i.v. dose todecrease hindquarters perfusion pressure (vasodilatation) by 15% isgiven as ED₁₅.

    ______________________________________                                        Compound of Example                                                                             ED.sub.15 (μm/kg)                                        ______________________________________                                        1                 0.05                                                        2                 0.38                                                        3                 0.64                                                        5                 0.24                                                        7                 0.15                                                        8                 0.04                                                        ______________________________________                                    

BRONCHODILATATION IN VIVO

Male guinea-pigs of the Dunkin Hartley strain (530 g±6 g) wereanaesthetised with Sagatal (pentobarbital sodium) (90 mg/kg i.p.).Airway resistance was measured using a modification of the classicalKonzett-Rossler technique (Versuchsanordnung zu Untersuchungen an derBronchialmuskulatur. Naunyn-Schmiedebergs Arch. Exp. Path. pharmak.,195: pp 71-74, (1940)). A dose of histamine which gave approximately150% increase in airway resistance was selected for i.v. administration.Bolus doses of the compound of Example 1 were administered (i.v.) oneminute before the histamine challenge.

The compound of Example 1 reduced the histamine-inducedbronchoconstriction. The threshold dose for this compound was 1×10⁻⁸mol/kg. The dose of the compound of Example 1 which reduced thehistamine hronchoconstriction by 50% (ED₅₀) was 1.8×10⁻⁶ mol/kg,demonstrating in-vivo anti-bronchoconstrictor activity.

PLATELET AGGREGATION INHIBITION IN VITRO

Platelet rich plasma (PRP) was prepared from whole human bloodanti-coagulated with 1/10 volume acid citrate dextrose. The citratedblood was centrifuged at 700 g for 5 minutes and the PRP removed. Theremaining red cells and plasma were centrifuqed for a further 15 minutesat 900 g and the platelet poor plasma removed. This was then mixed withthe PRP to give a final platelet count of 2-3×10⁸ cells/ml.

PRP was divided into 0,5 ml aliquots which were preincubated for 2minutes to 37° C. before being placed in the sample chamber of an HGaggregometer connected to a Teckman chart recorder

Aspirin was added to a concentration of 100 μM.

Aggregation to the endonecoxide mimetic U44069 (9,11-epoxymethano-PGH₂)was then examined in the absence and presence of a range ofconcentrations of the compound of Example 1.

The compound of Example 1 inhibited aggregation induced by theendoperoxide mimetic U44069 (10 μM) in asprin-treated platelet richplasma with an IC₅₀ value of 0.08±0.01 μM.

DESCRIPTION 1 (+) and (-)-6-(4-Aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone

Racemic 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H) -pyridazinone (2.0g) dissolved in a mixture cf acetonitrile (80 ml) and dichloromethane(30 ml) was added to a column of ionically bound(R)-N-(3,5-dinitrobenzoylphenyl)glycine on 40 μm γ-aminopropyl silanizedsilica (2.1 kg), packed at 1104 kPa (160 p.s.i.) (by slurrying withdichloromethane (1.5 L)) in a Jobin-Yvon medium pressure liquidchromatography system. The column was eluted withdichloromethane/methanol (199:1) over 9 hours at a rate of 80 ml min⁻¹.Detection was by u.v. at 280 nm. A broad peak was obtained from whichfractions were collected. The earlier fractions were enriched (-)enantiomer. These fractions were combined and re-chromatographed throughthe same column with the same eluant.

The selected column fractions were evaporated, triturated with diethylether, filtered and the resultant solid washed with diethyl ether anddried at 80° C. for 18 hours to give(-)-6-(4-aminophenyl)-5-methyl-4,5-dihydro -3(2H)-pyridazinone, inapproximately 100% enantiomeric excess, m.p. 203-4° C.; [α]²⁵ _(D=-)399° [concentration 0.74% in ethanol:water:conc. HCI (17:2:1)].

A sample of the (-) isomer was reacted with 3-bromopropionyl chloride toafford enantiomerically pure(-)-6-[4-(3-bromopropionamido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, the absolute configuration of which was shown by aX-ray diffraction study to be (R).

The later fractions from the first column were enriched (+) enantiomer(approximately 75% enrichment) which was subjected to medium pressureliquid chromatography (Jobin-Yvon system) over a column of ionicallybound (S)-N-(3,5-dinitrohenzoyl)phenylglycine on 25-40 μm γ-aminopropylsilanized silica (55 g) eluting with dichloronethane/methanol (199:1).The appropriate fractions were combined with fractions from another runand re-chromatographed through the same column.

The selected column fractions were evaporated, triturated with diethylether, filtered and the resultant solid washed with diethyl ether anddried at 80° C. for 18 hours to give(+)-6-(4-aminophenyl)-5-methyl-4,5-dihydro -3(2H)-pyridazinone, inapproximately 100% enantiomeric excess, m.p. 206-8° C.; [α]²⁵ _(D=+)376° [concentration 0 74% in ethanol:water:conc. HCl (17:2:1)].

EXAMPLE 15-Methyl-6-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone

A stirred mixture of6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (1.0 g),4H-pyran-4-one (0.52 g), water (20 ml), and concentrated hydrochloricacid (0.41 ml) was heated under reflux for 31/2 hours. The resultantsolid was dissolved in the minimum of hot water and the solution wasneutralised with aqueous ammonia to give the crude product, 1.16 g, m.p.249-256° C. The product was recrystallised first from water to which alittle 2N NaOH was added, and then from water alone to give the puretitle compound, 0.82 g, m.p. 254-256° C. (after melting andresolidifying at about 150° C.).

EXAMPLE 2 6-[4-(4-Oxo-1,4-dihydroovridin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone

A stirred mixture of 6-(4-aminophenyl)-4,5-dihydro -3(2H)-pyridazinonehydrochloride (1.5 g). 4H-pyran-4-one (0.7 g), and water (20 ml), washeated under reflux for 41/2 hours. The resultant solid was dissolved inthe minimum of hot water and the solution was neutralised with ammoniato give the crude product. Recrystallisation from water gave the titlecompound, 0.73 g, m.p. 270-272° C.

EXAMPLE 3 6-[4-(4-Oxo-1,4-dihydropyridin-1-yl)phenyl]-3(2H)-pyridazinone

A stirred mixture of 6-(4-aminophenyl)-3(2H) -pyridazinone hydrochloride(1.5 g), 4H-pyran-4-one (0.71 g), and water (20 ml), was heated underreflux for 2 hours. The pH of the hot solution was adjusted to 8 withaqueous ammonia and the mixture was cooled to give the crude product,1.84 g, m.p. 338-340° C. Recrystallisation from aqueous ethanol gave thetitle compound, 1,4 g, m.p. 339-341° C.

EXAMPLE 4 2-[4-(4-Oxo-1,4-dihydropyridin-1-yl)phenyl]-4H,6H-1,3,4-thiadiazin-5-one

A stirred mixture of 2-(4-aminophenyl)-4H,6H-1,3,4-thiadiazin-5-one (1.0g), 4H-pyran-4-one (0.51 g). water (20 ml ) and concentratedhydrochloric acid (0.42 ml), was heated under reflux for 3 hours. Thewarm solution was neutralised with concentrated aqueous ammonia andcooled to give a solid, 1.33 g. Recrystallisation from methanol gave thetitle compound, 0.89 g, m.p. 289-291° C.

EXAMPLE 5 2-[4-(4-Oxo-1,4-dihydropyridin-1-yl)phenyl]-4H,6H-1,3,4-oxadiazin-5-one

In a similar manner to that of Example 4, 2-(4-aminophenyl)-4H,6H-1,3,4-oxadiazin-5-one (1,4 g), gave a crude product which wasrecrystallised from ethanol to give the title compound. 0.48 g. m.p,decomposed >290° C.

EXAMPLE 6 6-[4-(4-Oxo=1,4-dihydropyridin-1-yl)phenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one

In a similar manner to that of Example 4, but under a nitrogenatmosphere, 6-(4-aminophenyl)-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.7g) gave a solid, 0.95 g. m.p. 285-290° C. (dec). Recrystallisation fromaqueous ethanol gave the title compound 0.67 g, m.p. 334-335° C. (dec).

EXAMPLE 7 6-[4-(4-Oxo-1,4-dihydropyridin-1-yl)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one

In a similar manner to that of Example 6, 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.7 g), gave a solid(0.83 g), m.p. 314-317° C. (dec). Recrystallisation from aqueous ethanolgave the title compound, 0.57 g, m.p. 330-331° C. (dec).

EXAMPLE 8 7-(4-Oxo-1,4-dihydropyridin-1-yl)-9a-methyl-9,9a-dihydroindeno[1,2-e][1,3,4]thiadiazin-2(3H)-one

A stirred mixture of 7-amino-9a-methyl-9,9a-dihydroindeno[1,2-e][1,3,4]thiadiazin-2(3H)-one hydrochloride (1.4 g), 4H-pyran-4-one(0.55 g) and water (20 ml) was heated under reflux for 51/2 hours. Apartial solution of the crude solid in hot water was neutralised withaqueous ammonia, and the resultant solid was recrystallised twice fromaqueous dimethylformamide to give the title compound 0.45 g, m.p.decomposed >250° C.

EXAMPLE 9 7-(4-Oxo-1,4-dihydropyridin-1-yl)-9 9a-dihydroindeno-1,2-e][1,3,4]thiadiazin-2(3H)-one

In a manner similar to that of Example 8, 7-amino-9,9a-dihydroindeno[1,2-e][1,3,4]thiadiazin-2(3H)-one hydrochloride (1.0g) gave a solid. 0.87 g, which was recrystallised from aqueous aceticacid to give the title compound, 0.38 g. m.p. decomposed >245° C.

EXAMPLE 10 5-[4-(4-Oxo-1,4-dihydropyridin-1-yl)phenyl]-6-methyl-3H,6H-1,3,4-thiadiazin-2-one

A stirred mixture of 5-(4-aminophenyl)-6-methyl-3H,6H-1,3,4-thiadiazine-2-one (0.54 g). 4H-pyran-4-one (0.26 g), glacialacetic acid (0.15 g) and water (20 ml) was heated under reflux for 24hours to give a solid. 0.54 g. Recrystallisation from aqueous ethanolgave the title compound, 0.28 g, which darkened at 265° C. and sublimedat 273-275° C.

EXAMPLE 11 5-[4-(4-Oxo-1,4-dihydropyridin-1-yl)phenyl]-2(1H)-pyrazinone

A stirred mixture of 5-(4-aminophenyl)-2(1H)pyrazinone hydrochloride(1.5 g, from hydrolysis of the corresponding acetamido derivative withhydrochloric acid) 4H-pyran-4-one (0.71 g) and water (15 ml) was heatedunder reflux for 21/2 hours under a nitrogen atmosphere. The resultantsolution was neutralised to give a solid, 1.79 g, m.p. 345° C. (dec).Recrystallisation from aqueous ethanol gave the title compound. 0.93 g.m.p. 354-357° C. (dec).

EXAMPLE 127-(4-Oxo-1,4-dihydropyridin-1-yl)-[5H1indeno[1,2-c]-pyridazin-3(2H)-one

A stirred mixture of 7-amino-[5H]indeno[1,2-c]-pyridazin-3(2H)-onehydrochloride (1.0 g) and 4H-pyran-4-one (0.48 g) in water (10 ml) washeated under reflux for 1 hour in a nitrogen atmosphere. The warmmixture was neutralised with aqueous ammonia to give a solid, 0.9 g,m.p. >300° C. This solid was triturated with warm dilute hydrochloricacid and washed with water to give the title compound, 0.42 g m.p. >300°C.

EXAMPLE 13 8-(4-Oxo-1,4-dihydropyridin-1-yl)-4,4a,5,6-tetrahydrobenzo[h1cinnolin-3(2H)-one

A stirred mixture of 8-amino-4,4a,5 6-tetrahydrobenzo[h]cinnolin-3(2H)-one hydrochloride (1.5 g) and 4H-pyran-4-one (0.84 g)in water (40 ml) was heated under reflux for 2 hours in a nitrogenatmosphere. The resultant solid was washed with dilute hydrochloric acidto give a crude product, 0.5 g. Purification by column chromatography(silica gel, 9:1 chloroform:methanol) gave the title compound 0.18 g.m.p. >300° C.

EXAMPLE 145-[4-(4-Oxo-1,4-dihydropyridin-1-yl)phenyl]-1,3,4-thiadiazol-2(3H)-one

i) A solution of 5-(4-nitrophenyl)-1,3,4-thiadiazol -2(3H)-one (2.82 g)and sodium sulphide (2.53 g) in dioxane (20 ml) and water (20 ml) wasstirred at 85° C. for 21/2 hours. The pH of the cooled reaction mixturewas adjusted to 14 with aqueous sodium hydroxide (2N) and the resultantsolution was extracted with dichloromethane (3×20 ml). The aqueous phasewas neutralised with dilute hydrochloric acid and the resultant paleyellow solid was recrystallised from aqueous hydrochloric acid to afford5-(4-aminophenyl) -1,3,4-thiadiazol-2(3H)-one hydrochloride, 1.65 g,m.p. >250° C.

ii) A mixture of 5-(4-aminophenyl)-1,3,4-thiadiazol -2(3H)-onehydrochloride (1,25 g). 4H-pyran-4-one (0.58 g), ethanol (10 ml) andwater (50 ml) was stirred under reflux under nitrogen for 31/2 hours.The cooled reaction mixture was filtered and the collected orange solidwas washed with aqueous potassium hydrogen carbonate and water and wasdried. The crude product (1,35 q) was treated with boilingdimethylformamide (200 ml) and the resultant suspension was cooled andfiltered. The collected solid was washed with ethanol and ether, driedand suspended in water (100 ml). Sufficient aqueous sodium hydroxide(2N) was added to the suspension to form a solution which was filtered.The filtrate was acidified to pH 6 with hydrochloric acid which causedthe precipitation of the title compound as a yellow solid, 0.96 g, m.p.343-4° C. (decomp).

EXAMPLE 15 5-[4-(4-Oxo-1,4-dihydropyridin-1-yl)phenyl]-13,4-oxadiazol-2(3H)-one

i) A solution of methyl 4-nitrobenzoate (20 g) and hydrazine hydrate (11g) in ethanol (200 ml) was stirred under reflux for 5 hours to afford4-nitrobenzoyl hydrazide 16.8 g, m.p. 217-219° C.

ii) A solution of carbonyldiimidazole (2.87 g) and 4-nitrobenzoylhydrazide (1,32 g) in dimethylformamide (30 ml) was stirred at 100° C.for one hour. The solvent was removed by evaporation and the resultantsolid was recrystallised from ethanol to afford 5-(4-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one, 0.75 g, m.p. 251-252° C.

iii) 5-(4-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one, (0.65 g) in ethanol(100 ml) was hydrogenated at 276 kPa (40 p.s.i.) in the presence ofpalladium on carbon ar room temperature for one hour. The reactionmixture was filtered, the filtrate was evaporated to dryness and theresultant yellow solid was recrystallised from ethanol to afford(5-(4-aminophenyl)-1,3,4-oxadiazol-2(3H)-one, 0.46 g, m.p. 172-173° C.

iv) A mixture of 5-(4-aminophenyl)-1,3,4-oxadiazol -2(3H)-one (0.41 g),4H-pyran-4-one (0.24 g). and hydrochloric acid (2N, 1.15 ml) in water(25 ml) was stirred under reflux for 3 hours to afford a yellow solid.This solid was added to hot water with stirring and the resultingsuspension was made alkaline (pH 8) with aqueous ammonia and was thenfiltered. The collected solid was dissolved in aqueous potassiumcarbonate and the resulting solution was neutralised with dilute aceticacid to afford an emulsion from which after centrifugation was obtainedthe title compound, 0.47 g. m.p. 220° C. (decomp), contaminated withpotassium acetate.

EXAMPLE 16(R)-5-Methyl-6-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone

A mixture of (R)-6-(4-aminophenyl)-5-methyl-45-dihydro-3(2H)-pyridazinone (100 mg), 4H-pyran-4-one (52 mg) andhydrochloric acid (0.1 N, 1 ml) in water (1,3 ml) was stirred underreflux under nitrogen for 3 hours. Aqueous ammonia (880, 0.01 ml) wasadded to the cooled reaction mixture to afford the title compound whichwas collected, washed with water and dried, 91 mg, m.p. 257-8° C.(softens 120° C.), [α]²⁵ _(D=-) 369.5° (1.07% in dimethylformamide).

EXAMPLE 17(S)-5-Methyl-6-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone

A mixture of(S)-6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (147 mg),4H-pyran-4-one (78 mg) and hydrochloric acid (0.1 N, 1.5 ml) in water (2ml) was stirred under reflux under nitrogen for 3 hours. The reactionmixture was cooled to afford the title compound, which was collected,washed with water and dried, 110 mg, m.p. 256-7° C. (softens 80° C.),[α]²⁵ _(D=+) 354° (1.03% in dimethylformamide).

EXAMPLE 185-Methyl-6-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone

i) A solution of 2-chloropropionyl chloride (49 ml) in dichloromethane(50 ml) was added to a mixture of anhydrous aluminium trichloride (55.5g) in dichloromethane (120 ml). The mixture was stirred for 10 minutesat room temperature and then a solution of fluorobenzene (39.5 ml) indichloromethane (30 ml) was added dropwise. The resulting mixture wasstirred for one hour, allowed to stand for 16 hours and then poured onto an icehydrochloric acid mixture. The two phase mixture was vigorouslystirred at room temperature for 11/2 hours, separated and the aqueouslayer washed with dichloromethane (2×50 ml). The combined organicextracts were then washed with aqueous sodium hydroxide (3N, 2×100 ml),water (1×100 ml) and brine (1×100 ml), dried (MgSO₄) and evaporatedunder reduced pressure to afford2-chloro-1-(4-fluorophenyl)-1-propanone, 71.3 g.

ii) Sodium hydride (50% oil dispersion, 3,5 g) was added with caution toa cooled solution of diethyl malonate (11.85 ml) in dimethylformamide(10 ml). The reaction mixture was stirred at room temperature for 30minutes before a solution of 2-chloro-1-(4-fluorophenyl)-1-propanone(12.13 g) in dimethylformamide (50 ml) was added in small aliquots. Theresulting reaction mixture was stirred for 2 hours at room temperatureand then water (35 ml) was added. The mixture was extracted withpetroleum ether (b.p. 40-60° C. ) (3×50 ml) and the combined organicextracts were evaporated under reduced pressure to afford ethyl2-ethoxycarbonyl-3-(4-fluorobenzoyl) butanoate (15.92 g).

iii) Aqueous hydrochloric acid (50%, 50 ml) was added to a solution ofpart of the product from ii) (10 g) in dioxan (50 ml). The resulting twophase mixture was stirred under reflux for 28 hours, cooled andextracted with dichloromethane (3×50 ml). The combined organic extractswere washed with aqueous sodium hydroxide (2N, 1×100 ml, 2×50 ml) andthe combined basic washings were acidified with concentratedhydrochloric acid to pH 1. The acidified aqueous mixture, containing aprecipitated oil, was extracted with dichloromethane (3×50 ml). Thedichloromethane extracts were combined, washed with water, dried (MgSO₄)and evaporated to dryness yielding an oil (4.87 g) which on triturationwith cyclohaxane afforded 3-(4-fluotobenzoyl)butanoic acid as a solidm.p. 75-78° C.

iv) A solution of 3-(4-fluorobenzoyl)butanoic acid (8 g),4-hydroxypyridine (8 g) and sodium hydroxide (4.6 g) in water (80 ml)was heated in an autoclave at 140° C. for 20 hours. The reaction mixturewas cooled and on acidification to pH3 with dilute hydrochloric acidafforded as a white crystalline precipitate 3-[4-(4-oxo-1,4-dihydropyridin-1-yl)benzoyl]butanoic acid, 9.45 g, m.p. 250-252° C.

v) Hydrazine hydrate (1.8 g) was added to a suspension of3-[4-(4-oxo-1,4-dihydropyridin-1-yl)benzoyl]-butanoic acid (5 g) inwater (60 ml). The resulting solution was stirred under reflux for 2hours and cooled to afford the title compound as a pale yellow solid,4.45 g. m.p. 255-258° C.

EXAMPLE 195-Methyl-6-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone

A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro -3(2H)-pyridazinone(101 mg), 1,5-bis(dimethylamino)-1,4-pentadien-3-one (84 mg) andhydrochloric acid (1N, 0.5 ml) in water (1.5 ml) was stirred at roomtemperature for 4 hours. More hydrochloric acid (1N, 0.5 ml) was addedand the reaction mixture was stirred at room temperature for 18 hoursand then under reflux for 4 hours to afford a quantity of red insolublematerial. The hot aqueous solvent was decanted off from the insolublematerial, was allowed to cool and was seeded to afford the titlecompound, 41 mg, m.p. 245-249° C.

EXAMPLE 20

A pharmaceutical composition for parenteral administration is preparedby dissolving the title compound of Example 1 (0.025 g) in water (100ml) with heating. The solution is cooled and is then sterilised byfiltration through a 0.22 micron membrane filter and sealed in sterilecontainers suitable for injections Ph. Eur.

Compositions containing the compound of Example 1 (0.05 g) in water (100ml) are prepared in analogous manner.

EXAMPLE 21

Pharmaceutical compositions for oral administration are prepared bycombining the following:

    ______________________________________                                                          % w/w                                                       ______________________________________                                        5-methyl-6-[4-(4-oxo-1,4-dihydro-                                                                 0.5      3.0    7.14                                      pyridin-1-yl)phenyl]-4,5-dihydro-                                             3(2H)-pyridazinone                                                            2% w/w Soya lecithin in soya                                                                      90.45    88.2   84.41                                     bean oil                                                                      Hydrogenated vegetable                                                                            9.05     8.8    8.45                                      shortening and beeswax                                                        ______________________________________                                    

The formulations are then filled into individual soft gelatin capsules.

What is claimed is:
 1. A compound of the formula (1): ##STR38## or apharmaceutically acceptable salt thereof, wherein A is a group ofsub-formula (a) or (b): ##STR39## X is NH; R² is hydrogen or methyl;R³is hydrogen; Y is NH; and R⁴ is hydrogen.
 2. A compound according toclaim 1 wherein a is a group of sub-formula (a).
 3. A compound accordingto claim 2 which is6-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one or a pharmaceutically acceptable salt thereof.4. A compound according to claim 2 which is6-[4-(4-oxo-1,4-dihydropyridin-1-yl)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one or a pharmaceutically acceptable salt thereof.5. A pharmaceutical composition which comprises a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 6. A pharmaceuticalcomposition according to claim 5 in unit dose form adapted for oraladministration.
 7. A method for stimulating cardiac activity in a hostin need thereof by administration of a non-toxic but effective amount ofa compound according to claim
 1. 8. A method for effectingbronchodilatation in a host in need thereof by administration of anon-toxic but effective amount of a compound according to claim
 1. 9. Amethod for effecting phosphodiesterase (type III) inhibition in a hostin need thereof by administration of a non-toxic but effective amount ofa compound according to claim
 1. 10. A method for treating congestiveheart failure in a host in need thereof by administration of a non-toxicbut effective amount of a compound according to claim 1.